Prostate cancer ablation

ABSTRACT

Methods and systems for delivering electrical energy and controlled, mild hyperthermia to a prostate tissue of a patient for destruction of cancerous and/or hyperplastic tissue. A method includes positioning a plurality of electrodes in a target tissue region comprising the prostate tissue, and establishing an alternating electrical current flow through a volume of the prostate tissue to induce mild heating and destruction of cancerous cells in the volume.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application No. 60/972,698 (Attorney Docket No.26533A-000700US), filed Sep. 14, 2007, the full disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to electric field delivery to aprostate tissue of a patient. More particularly, the present inventionprovides systems and methods for delivering alternating current andcontrolled, mild heating to a prostate tissue of a patient fordestruction of cancerous and/or hyperplastic tissue.

The prostate gland is a walnut-sized gland located in the pelvic area,just below the outlet of the bladder and in front of the rectum. Itencircles the upper part of the urethra, which is the tube that emptiesurine from the bladder. The prostate is an important part of malereproductive system, requiring male hormones like testosterone tofunction properly, and helps to regulate bladder control and normalsexual functioning. The main function of the prostate gland is to storeand produce seminal fluid, a milky liquid that provides nourishment tosperm, and increases sperm survival and mobility.

Cancer of the prostate is characterized by the formation of malignant(cancerous) cells in the prostate. Prostate cancer is the leading cancerrelated cause of death in men in the United States. There are currentlyover 2 million men in the United States with prostate cancer, and it isexpected that there will be approximately 190,000 new cases of prostatecancer diagnosed, with 28,000 men dying from the disease in 2008.

In addition to risks of morbidity due to prostate cancer, most men over60 years old experience partial or complete urinary obstruction due toenlargement of the prostate. This condition can originate from prostatecancer, or more typically, from benign prostatic hyperplasia (BPH),which is characterized by an increase in prostate size and cell massnear the urethra.

Common active treatment options include surgery and radiation. Surgeryoften includes the complete surgical removal of the prostate gland(“Radical Prostatectomy”), and in certain instances the regional lymphnodes, in order to remove the diseased tissue from the body. In someinstances, a nerve sparing prostatectomy is attempted in an effort tomaintain erectile function in the patient after treatment. Side effectsassociated with radical prostatectomy can include pain, inflammation,infection, incontinence, shorter penis and impotence.

Radiation therapy is another treatment option for prostate cancer and ischaracterized by the application of ionizing radiation to the diseasedarea of the prostate. Ionizing radiation has the effect of damaging acells DNA and limiting its ability to reproduce. For Prostate Cancertreatment, two methods of radiation therapy include External BeamRadiation Therapy (EBRT) and internal radiation, commonly known asBrachytherapy. EBRT involves the use of high-powered X-rays deliveredfrom outside the body. The procedure is painless and only takes a fewminutes per treatment session, but needs to be over extended periods offive days a week, for about seven or eight weeks. During EBRT, the rayspass through and can damage other tissue on the way to the tumor,causing side effects such as short-term bowel or bladder problems, andlong-term erectile dysfunction. Radiation therapy can also temporarilydecrease energy levels and cause loss of appetite.

Brachytherapy involves the injection of tiny radioactive isotopecontaining ‘seeds’ into the prostate. Once positioned in the tissue, theradiation from the seeds extends a few millimeters to deliver a higherradiation dose in a smaller area, causing non-specific damage to thesurrounding tissue. The seeds are left in place permanently, and usuallylose their radioactivity within a year. Internal radiation also causesside effects such as short-teen bowel or bladder problems, and long-termerectile dysfunction. Internal radiation therapy can also temporarilydecrease energy levels and cause loss of appetite. It is also common forthe implanted seeds to migrate from the prostate into the bladder andthen be expelled through the urethra during urination. Most significant,however, is the change in the texture of the prostate tissue over time,making the subsequent removal of the gland, as described above,complicated and difficult as a secondary treatment.

Given the significant side-effects with existing treatments such asradical prostatectomy and radiation therapy, less invasive and lesstraumatic systems and procedures have been of great interest. One suchmore minimally invasive system developed in recent years includes socalled “Trans-urethral Needle Ablation” or TUNA, which involves passinga radio-frequency (RF) device such as a catheter probe or scope into theurethra for delivery of high frequency energy to the tissue. The RFinstruments include electrode tips that are pushed out from the side ofthe instrument body along off-axis paths to pierce the urethral wall andpass into the prostatic tissue outside of the urethra. High-frequencyenergy is than delivered to cause high-temperature ionic agitation andfrictional heating to tissues surrounding the electrodes. Thehigh-temperature induced in the tissue, e.g., up to 90-100 degrees C. ormore, is non-specific to cancerous tissue and destroys both healthy andnon-healthy tissue.

Another technique developed in recent years for treating BPH isTrans-urethral Microwave Thermo Therapy (or “TUMT”). This techniqueinvolves use of a device having a microwave probe or antenna locatednear its distal end and connected to an external generator of microwavepower outside the patient's body. The microwave probe is inserted intothe urethra to the point of the prostate for energy delivery andmicrowave electromagnetic heating. Since the microwave probe deliverssubstantial heating that can cause unwanted damage to healthy tissues orto the urethra, devices typically make use of a cooled catheter toreduce heating immediately adjacent to the probe. The objective is tocarefully balance cooling of the urethra to prevent damage to it by theheating process, while at the same time delivering high temperatureheating (greater than 50 degrees C.) to the prostatic tissue outside ofand at a distance from the urethra. In this procedure, the prostatictissue immediately around the urethra and the urethra itself aredeliberately spared from receiving an ablative level of heating byattempting to keep the temperatures for these structures at less than 50degrees C. Unfortunately, controlling the tissue heating due to theapplied microwave energy is difficult and unintended tissue damage canoccur. Further, destruction of tissue beyond the cooled region isindiscriminate, and control of the treatment zone is imprecise andlimited in the volume of tissue that can be effectively treated.

Accordingly, there is a continuing interest to develop less invasivedevices and methods for the treatment of BPH and prostate cancer that ismore preferential to destruction of target tissue and more preciselycontrollable.

BRIEF SUMMARY OF THE INVENTION

The present invention provides systems, devices and related methods forapplying electric fields, which can be delivered for preferential and/orcontrollable cancerous cell destruction and tissue ablation. Methods anddevices of the present invention will generally be designed to advancean electrode or plurality of electrodes to a target tissue region andapply an electric field to the target tissue region. The electrode orplurality thereof can be positioned such that the applied electric fieldradiates throughout the target tissue region, including, for example,where the electric field radiates outwardly and in a plurality ofdirections, e.g., radially, through the target tissue. In certainembodiments, the energy is applied so as to deliver mild and controlledheating of the target tissue.

Thus, the present invention includes systems and devices, as well asmethods for delivering electric fields to prostate tissue. Electricfield delivery can include establishing an electric current flow througha target tissue region comprising prostate tissue so as topreferentially ablate or destroy cancerous cells in the target tissueregion.

For a fuller understanding of the nature and advantages of the presentinvention, reference should be made to the ensuing detailed descriptionand accompanying drawings. Other aspects, objects and advantages of theinvention will be apparent from the drawings and detailed descriptionthat follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a device according to an embodiment of the presentinvention.

FIGS. 2A through 2D illustrate a device according to another embodimentof the present invention.

FIGS. 3A through 3C illustrate a probe and electrode positioningrelative to a target tissue region according to several exemplaryembodiments of the present invention.

FIGS. 4A and 4B illustrate a system for delivery of electric fields to aprostate tissue of a patient using a plurality or array of electrodes.

FIGS. 5A and 5B shows a system for delivering electric fields to aprostate tissue of a patient using elongate electrode probes and a guidetemplate device.

FIGS. 6A through 6D illustrate field delivery in a target tissueaccording to various embodiments of the present invention.

FIG. 7 shows a flow chart illustrating energy delivery and therapeutictreatment of a patient's prostate tissue using differentially activatedelectrodes of an array.

FIGS. 8A through SC illustrate exemplary electrode embodiments.

FIG. 9 illustrates transurethral system and imaging system according toan embodiment of the present invention.

FIGS. 10A and 10B a transrectal energy delivery system and positioningof electrodes according to an embodiment t of the present invention.

FIG. 11 includes a diagram illustrating a system according to anembodiment of the present invention.

FIGS. 12A and 12B show study results illustrating tumor loss (FIG. 12A)and PSA levels (FIG. 12B) following treatment according to one aspect ofthe present invention.

FIG. 13 shows study results illustrating changes in tumor volumefollowing administration of electrical field therapy according to amethod of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides systems and devices, and related methodsfor prostate tissue ablation. According to the present invention, anelectrode or plurality of electrodes can be introduced into a targettissue region and an electric field applied to the target tissue regionfor controlled and/or preferential destruction of cancerous cells.

Various probe and electrode configurations and/or arrangements may beselected for use according to the present invention and may depend atleast partially on the nature and location of the target area. Oneembodiment of a probe configuration that has been demonstrated to beparticularly effective includes probes or electrode configuration withelectrodes positioned such that energy delivery includes generatingcurrent fields in a plurality of different directions throughout atreatment volume. Further, electrodes can be activated in a bipolarelectrical arrangement, including activation in pairs or groupcombinations, such that tissue disposed between electrodes or within atreatment volume substantially defined by the electrodes acts as amedium through which current field is established or as a currentpathway.

In one example, electrodes of a system include a plurality or array ofelectrodes that can be differentially activated in distinct groups orpairs for establishing different orientations of current fieldthroughout the target tissue. Electrodes can include a plurality ofseparately controlled electrodes or groups of electrodes, eitherphysically coupled together (e.g., attached to a housing, deployablefrom a probe, etc.) or can be uncoupled physically and individuallypositionable and electrically addressable. In some cases, electrodepositioning and activation can be selected to establish a current fieldthat is oriented radially through a inner or center of a treatmentvolume. For example, a probe can be configured such that an inner orcentrally located electrode is surrounded by radially spaced electrodesin a bipolar arrangement, and current flow established between the innerelectrode and the outer spaced electrodes. Alternatively, a flow centercan be established by defining a volume with positioned electrodes andactivating a series of opposing electrodes to establish radial currentflow through the volume and to destroy cancerous tissue. Regardless ofthe precise electrode configuration, in one aspect of the presentinvention, the applied therapeutic field can be contained substantiallywithin the desired treatment region or volume of the target tissue, withcurrent flowed through the target tissue radially or in a plurality ofdifferent directions.

Establishment and application of energy delivery utilizing the describedenergy parameters and/or field delivery (e.g., orientation) can offerseveral advantages. First, energy delivery according to the presentinvention further advantageously allows a more controlled or precisetherapeutic energy dose both in terms of delivery of the desired currentand resulting effects, as well as more accurate delivery to the targetor intended tissue. For example, current flow is established betweenelectrodes in a bipolar arrangement, with current flow established andsubstantially contained between the spaced electrodes. Further, tissueheating can be more precisely controlled to prevent or minimizeexcessive heating and/or hot spots that can cause unintended damage tohealthy or non-target tissues. For example, energy delivery can beselected (e.g., frequency ranges between about 50 kHz to about 300 kHz)such that tissue heating occurs significantly or predominately due totissue resistance, limiting or minimizing the high-frictional heatingobserved at high frequencies (e.g., 500 kHz or greater), the latter ofwhich can include significant tissue temperature gradients throughoutthe treated tissue, with drastic tissue temperature changes occurring asa function of electrode distance. While heating may occur due to bothtissue resistance and frictional heating, with relative reduction ofhigh friction type heating, a more constant and controlled heatingbetween opposing electrodes may be delivered.

In one aspect of the inventive methods, relative electrode positioningcan be selected so as to further allow more precise control of thedesired effect (e.g., induction of mild hyperthermia) of the appliedfield on the tissue. Factors such as differential conductive propertiesand resistance or tissue impedance (e.g., differences in muscle,adipose, vasculature, etc.), as well as differential perfusion of bloodthrough vascularized tissue, can effect the ability to control and/orpredict effects of delivered current field through certain tissues andvarying tissue volumes. Thus, in one embodiment, distances betweenactivated electrodes can controlled and in some cases confined toshorter distances, such as a few centimeters or less, for improvedcontrol and predictability of current effects (e.g., tissue heating,field delivery, field orientation, etc) on the targeted tissue.

Another advantage of the present inventive methods and systems is thatenergy delivery and application of mild hyperthermia as described hasbeen observed to be surprisingly effective in preferentially damagingand destroying cancerous cells compared to non-cancerous or healthycells/tissue. Preferential destruction, as described herein, refers toestablishing current flow as described with application of hyperthermia,generally below about 50 degrees C., such that cytotoxic effects oftreatment are, on average or as a whole, more destructive and/or lethalto cancerous or hyperplastic cells (e.g., cells exhibiting orpredisposed to exhibiting unregulated growth) compared to non-cancerousor healthy cells. In some instances, establishing current flow andinduction of mild hyperthermia as described herein is remarkablyeffective in preferentially destroying cancerous cells with limited orno observable damage to non-cancerous tissues.

Furthermore, and without being bound by any particular theory, electrodeconfiguration and field application as described in certain embodiments(e.g., radially and/or in a plurality of different directions) may takeadvantage of tumor or mitotic cell physiology to increase treatmenteffectiveness, and can include a more optimal or effective orientationof the applied field with respect to dividing cells of the targetregion. For example, energy application can be accomplished such thatcurrent fields are substantially aligned at some point during energydelivery with division axes of dividing cells (e.g., cancerous cells),thereby more effectively disrupting cellular processes or mitotic events(e.g., mitotic spindle formation and the like). As cancerous cells aredividing at a higher rate compared to non-cancerous cells, fieldapplication in this manner may preferentially damage cancerous cellscompared to healthy or non-dividing cells. It will be recognized,however, that energy application likely has several or numerouscytotoxic effects on cells of the target region and that such effectsmay be cumulatively or synergistically disruptive to a target cell,particularly to cells disposed or pre-disposed to unregulated growth(i.e., cancerous cells). Other cytotoxic or disruptive effects of theenergy application as describe herein may occur due, for example, toapplication of mild hyperthermia (e.g., mild heating of tissue betweenabout 40 to 48 degrees C.; or less than about 50 degrees C.); iondisruption, disruption of membrane stability, integrity or function; andthe like.

As discussed above, various electrode or probe configurations can beutilized according to the present invention. In one embodiment,electrodes can include an array of needle electrodes, which can be fixedto common support (e.g., housing) or separately positionable andcontrolled. Such a plurality or array of electrodes can include astraight-needle array including electrically conductive material such asstainless steel, gold, silver, etc. or combination thereof. An array ofstraight-needle electrodes can be coupled to a rigid needle support orhousing that can ensure correct positioning of each individual needlerelative to the others. The needles can be arranged parallel to oneanother with opposing rows and/or columns of electrodes ensuring thefield is delivered to and contained within the target area. Needlelength and needle spacing can vary depending on the actual dimensions ofthe target tissue. Individual needle placement can be guided usingimaging (e.g., ultrasound, X-ray, etc.) and relative needle position canbe maintained with a rigid grid support (e.g., housing, template, etc.)that remains outside the body. The needle assembly will electricallyconnect to the control system or module, e.g., via insulated wires andstainless steel couplings.

In another embodiment, a probe can include one or more electrodes thatare deployable from an elongate probe housing or catheter. Suchembodiments may be particularly useful for treatment of target areasmore difficult to access with an array of fixed needles. Such deployabletype probes, and others described herein, can be inserted percutaneouslythrough the skin of the patient and into the target tissue, As above,appropriate imaging technology can be used to guide the preciseplacement of the probe in the target site, In one embodiment, adeployable type probe can include outer polyurethane sheath housingpre-shaped deployable shape memory metal tines and a stainless steelcentral electrode tip. Conductive surfaces can further be coated with ahighly conductive material.

Another embodiment of the probe can include one or more expandableelements (e.g., balloon) that can be individually positioned around atarget area or organ and then deployed and “inflated” to achieve maximumsurface area and optimal distribution of the therapeutic field. In oneexample, an electrically active segment of the expandable element caninclude an electrically conductive material (e.g., silver, gold, etc.)coated or deposited on a mylar balloon. Prior to deployment andinflation, the expandable element can be contained inside a flexiblecatheter that can be guided to the treatment area. Once the deliverycatheter is positioned, the “balloon” can be deployed and expanded viathe circulation of fluid through the balloon, which can have a selectedor controlled temperature and may act as a heat sink. The therapeuticfield can than be delivered via the silver coating on the mylar balloon.Two or more probes deployed in this fashion will serve to contain thefield within the treatment area.

Electrodes and probes of the present invention can be coupled to controlsystem or control module designed to generate, deliver, monitor andcontrol the characteristics of the applied field within the specifiedtreatment parameters. In one embodiment, a control system includes apower source, an alternating current (AC) inverter, a signal generator,a signal amplifier, an oscilloscope, an operator interface and/ormonitor and a central processing unit (CPU). The control unit canmanually, automatically, or by computer programming or control, monitor,and/or display various processes and parameters of the energyapplication through electrodes and to the target tissue of the patient.While the control system and power source can include various possiblefrequency ranges, current frequency delivered to target tissue will beless than about 300 kHz, and typically about 50 kHz to about 250 kHz.Frequencies in this range have been observed as effective in preciselycontrolling the energy application to the target tissue, controllingthermal effects primarily to mild thermal application, andpreferentially destroying cancerous cells with limited or no observabledamage to non-cancerous tissues.

Energy application according to the present invention can furtherinclude mild or low levels of hyperthermia. In some embodiments, smallchanges/elevations in temperature in the target tissue region may occur,but will typically be no more than about 10 degrees C. above bodytemperature, and may be about 2 degrees to less than about 10 degrees C.above body temperature (e.g., normal human body temperature of about 38degrees C.). Thus, local tissue temperatures (e.g., average tissuetemperature in a volume of treated tissue) during treatment willtypically be less than about 50 degrees C., and typically within a rangeof about 40-48 degrees C. In one embodiment, average target tissuetemperature will be selected at about 42-45 degrees C. As target tissuetemperatures rise above about 40-42 degrees C. curing treatment, thecytotoxic effects of energy delivery on cancerous cells of the targetregion are observably enhanced, possibly due to an additive and/orsynergistic effect of current field and hyperthermic effects. Where mildhyperthermic effects are substantially maintained below about 48 degreesC., the energy delivery according to the present invention appears tomore preferentially destroy cancerous cells compared to healthy ornon-cancerous cells of the target tissue region. Where energy deliveryinduces tissue heating substantially in excess of about 45-48 degrees C.(e.g., above about 48-50 degrees C.), the preferential cytotoxic effectson cancerous cells may begin to diminish, with more indiscriminatedestruction of cancerous and non-cancerous cells occurring. Thus, asignificant advantage of treatment methods according to the presentinvention includes the ability to precisely and accurately controlenergy delivery and induced hyperthermic effects, such that tissuehyperthermia can be accurately controlled and maintained in a desiredtemperature range(s) e.g., temperature ranges selected for more targetedor preferential destruction of cancerous cells compared to non-cancerouscells.

Tissue temperatures can be selected or controlled in several ways. Inone embodiment, tissue temperatures can be controlled based on estimatedor known characteristics of the target tissue, such as tissueimpedance/conductivity, tissue volume, blood flow or perfusioncharacteristics, specific heat capacity of the tissue, tissue density,and the like, with energy application to the tissue selected to deliveran approximated controlled mild increase in tissue temperature. Inanother embodiment, tissue temperature can be actively detected ormonitored, e.g., by use of a thermosensor feedback unit, duringtreatment, with temperature measurements providing feedback control ofenergy delivery in order to maintain a desired target tissue temperatureor range. Temperature control measures can include electronics,programming, thermosensors, thermocouples, and the like, coupled with orincluded in a control unit or module of a system of the invention.

Energy application and induction of hyperthermia in a target tissueregion according to the present application can include delivery ofvarious types of energy delivery. As described, application of generallyintermediate frequency range (e.g., less than about 300 kHz) alternatingcurrent in the RF range has been observed as effective in establishingmild heating and hyperthermia, as well as current fields in a controlledmanner so as to provide a cytotoxic effect, and in some instances, apreferential destructive effect to cancerous cells of a target tissuevolume/region. It will be recognized, however, that additional energyapplications and/or ranges may be suitable for use according to thepresent invention, and that systems and methods of the present inventionmay be amenable to use with other or additional energy applications. Forexample, energy application can include current flow having frequenciesfound generally in the RF range, as well as microwave range, includinghigher frequencies such as 300-500 kHz and above, and may further beamenable to use with direct current applications. Applied current can bepulsed and/or continuously applied, and energy delivery can be coupledwith a feedback-type system (e.g., thermocouple positioned in the targettissue) to maintain energy application and/or tissue heating in adesired range. Methods of the present invention can include any one ormore (e.g., combination) of different energy applications, inducedtemperatures, etc. as described herein.

In certain embodiments, particularly where energy application isselected for lower power delivery/ablation, the control system can bedesigned to be battery powered and is typically isolated from ground. Insuch an embodiment, AC current is derived from the integrated powerinverter. An intermediate frequency (e.g., less than 300 kHz; or about50 kHz to about 250 kHz) alternating current, sinusoidal waveform signalis produced from the signal generator. The signal is then amplified, inone non-limiting example, to a current range of 5 mA to 50 mA andvoltage of up to 20 Vrms per zone. Field characteristics includingwaveform, frequency, current and voltage are monitored by an integratedoscilloscope. Scope readings are displayed on the operator interfacemonitor. An integrated CPU monitors overall system power consumption andavailability and controls the output of the signal generator andamplifier based on the treatment parameters input by the operator. Theoperator can define treatment parameters to include maximum voltage,maximum current or temperature, maximum power, and the like. In anotherembodiment, the applied field can be cycled on and off, e.g., at a highrate, to keep the temperature relatively constant and with the dutycycle (e.g., on time—off time) adjusted to accurately controltemperature.

Imaging systems and devices can be included in the methods and systemsof the present invention. For example, the target tissue region can beidentified and/or characterized using conventional imaging methods suchas ultrasound, computed tomography (CT) scanning, X-ray imaging, nuclearimaging, magnetic resonance imaging (MRI), electromagnetic imaging, andthe like. In some embodiments, characteristics of the tumor, includingthose identified using imaging methods, can also be used in selectingablation parameters, such as energy application as well as the shapeand/or geometry of the electrodes or array of electrodes. Additionally,these or other known imaging systems can be used for positioning andplacement of the devices and/or electrodes in a patient's tissues.

A target tissue will include prostate tissue or tissue includingcancerous prostate cells and/or hyperplastic tissue of the prostate orprostate region. Thus the present invention includes delivery ofelectrical fields and ablation therapy to a target tissue includingprostate tissue by making use of the techniques, systems and probesdescribed herein. Prostate tissue can be accessed for delivery ofelectrical fields as described herein can by using a variety of methods.For example, prostate tissue access can include any of a variety ofcurrently know access/surgical methods used for existing prostatetreatment techniques, which will be modified for delivery of theablation treatment as described herein. Surgical access can include, forexample, techniques commonly employed for surgical intervention forprostate cancer that involves radical prostatectomy via an abdominal(retropubic) or perineal approach, or various robotic methods. Ratherthan removing the prostate tissue via surgical excision, however,electrodes of a probe according to the present invention can bypositioned in the target tissue including prostate cells/cancerous cellsand current applied to the tissue as described herein. While the presenttechniques can provide an alternative therapy to other techniques suchas radical prostatectomy, in some cases other surgical techniques canoptionally be used in addition or conjunction with the ablationtechniques of the present invention. For example, treatment may first bedelivered via ablation therapy of the present invention and followed(e.g., at a later time) by other surgical techniques, such as partial orentire prostatectomy. Such an approach may in some instances improveoutcomes and/or reduce complications commonly associated with othertreatments such as surgical removal of the prostate, e.g., by reducingthe amount of tissue in need of surgical removal.

Other known prostate tissue access techniques besides more traditionalsurgical access can be employed in delivery of ablation therapy of thepresent invention. For example, surgical techniques commonly used inhyperthermic ablation methods can be employed for ablation therapyaccording to the present invention, including various transurethralaccess methods, such as those commonly employed in transurethral needleablations, transurethral microwave ablation, ultrasound (high-intensityfocused ultrasound), electrical vaporization (transurethral electricalvaporization of the prostate), and the like. Various other techniques,including minimally invasive techniques, can be employed, includinglaparoscopic techniques (e.g., percutaneous puncture/laparoscopictechniques), transrectal access or puncture, and the like. Variousmonitoring techniques can be used in conjunction with ablation. Forexample, imaging systems and devices (see, e.g as described below),diagnostic monitoring (e.g., prostate-specific antigen (PSA) testing),etc. can be used to evaluate and/or monitor disease state and/ortreatment progression.

Thus, energy delivery probes, according to the present invention, can beadvanced and positioned according to various prostate tissue accesstechniques. Methodologies and access techniques, as noted above, caninclude without limitation open surgical techniques, laparoscopic orminimally invasive surgical access, puncture and/or advancement (e.g.,percutaneous puncture) of probes and/or electrodes through the perineum,as well as transurethral and/or transrectal access. Exemplary probeconfigurations and positioning, according to certain embodiments of thepresent invention, are generally described further below.

Referring to FIG. 1, a device according to an embodiment of the presentinvention is described. The device 10 includes a delivery member 12having a distal portion 14 and a proximal portion 16. The device 10further includes a proximal portion 18 of the device that can be coupled(e.g., removably coupled) to the delivery member 12. Additionally, thedevice 10 can include conductive cables 20 electrically coupled to anenergy source (not shown). The device includes a plurality of electrodes22 at the distal portion 14 of the delivery member 12. The electrodes 22can be positioned or fixed, for example, at the distal end of thedelivery member 12 or positionable and deployable from a lumen of thedelivery member 12 and retractable in and out of the distal end of thedelivery member 12. The electrodes 22 can include a non-deployed state,where the electrodes 22 can be positioned within a lumen of the deliverymember 12, and a deployed state when advanced from the distal end of thedelivery member 12. Electrodes 22 are advanced out the distal end anddistended into a deployed state substantially defining an ablationvolume.

In another embodiment, a probe can include a plurality of needleelectrodes fixed to or positioned on a body or housing of a device.FIGS. 2A through 2C show a device having a plurality of electrodescoupled to a housing, according to another embodiment of the presentinvention. As shown, the device 30 includes a plurality of electrodesextending from the distal portion (e.g., housing) of the device. FIG. 2Ashows a three dimensional side view of the device having the pluralityof electrodes. FIG. 2B shows a top view of the device illustrating theelectrode arrangement. The plurality includes a centrally positionedelectrode 32 and outer electrodes 34, 36, 38 spaced laterally from thecentral electrode 32. The illustrated electrodes include substantiallylinear needle-like portions or needle electrodes. The electrodes extendfrom the distal portion of the device and are oriented to besubstantially parallel with the longitudinal axis of the device 30.Additionally, each electrode is substantially parallel with otherelectrodes of the plurality. The plurality of electrodes substantiallydefine the ablation volume, with the outer electrodes 34, 36, 38substantially defining a periphery of the ablation volume and theelectrode 32 positioned within or at about the center point of thedefined periphery. Each of the electrodes can play different roles inthe ablation process. For example, there can be changes in polarityand/or polarity shifting between the different electrodes of the device.As with other devices of the invention, electrodes can be electricallyindependent and separately addressable electrically, or two or moreelectrodes can be electrically connected, for example, to effectivelyfunction as one unit. In one embodiment, for example, outer electrodes34, 36, 38 can be electrically connected and, in operation, include apolarity different from that of the inner electrode 32. As illustratedin FIG. 2C the electrodes 32 and 34, 36 of the device can includeopposing charges (e.g., bipolar). In such an instance, the appliedelectrical current can provide an electrical field, as illustrated bythe arrows, extending radially outward from the central electrode 32 andtoward the peripherally positioned or outer electrode(s) 34, 36. FIG. 2Dillustrates the concept of a current flow center, where current flow isestablished through about a center location of a treatment volume.

In use, as shown in FIGS. 3A through 3C, a device 42 of the presentinvention can be advanced through the patient's tissue 44, and anelectrode 46 of the device 42 positioned within a target tissue region48 (e.g., prostate tissue). Once the electrode 46 is positioned in thetarget tissue region 48, electrical current is delivered to the targettissue region 48 or treatment region. As the electrode 46 is positionedwithin the target tissue region 48, the applied electrical current canprovide an electric field that radiates outward and in a plurality ofdirections. In a bipolar mode embodiment, outer electrodes substantiallydefining an ablation volume can function as return electrodes, orcomplete a circuit with an electrode(s) positioned within the ablationvolume, with applied current flowing through tissue of the target regionpositioned between the outer electrodes and electrode(s) positionedwithin the ablation volume. FIG. 3C shows use of a deployable electrodedevice 50 of the present invention according to another embodiment ofthe present invention. As described above, the device 50 is advancedthrough the patient's tissue 62 and the delivery member 52 positionedproximate to the target tissue region 54. Once the delivery member 52 ispositioned, a plurality of electrodes 56, 58, 60 can be deployed fromthe delivery member 52. Outer electrodes 56, 58 are deployed within oraround the perimeter of the target tissue region 54, e.g., at about themargin of the target tissue region (e.g., tumor margin) andsubstantially define the ablation volume or target region. The innerelectrode 60 is positioned within the ablation volume.

In another embodiment of the present invention, systems and methods caninclude a plurality of electrodes (e.g., needle electrodes) that can beindividually advanced and positioned in the target/prostate tissue, andelectrically activated for energy delivery (see, e.g., FIG. 4 below). Insuch an embodiment, an array of electrodes can be advanced through theperineum of the patient and electrically activated (e.g., differentiallyactivated) to deliver current field in a plurality of differentdirections. An array or plurality as described can include variousnumbers of electrodes, and the selected number can depend, at leastpartially, on factors such as target tissue characteristics, treatmentregion, needle size, and the like. An array can include a few to severaldozen electrodes. In one example, an array can include about a fewelectrodes to about a dozen or more (e.g., 10-100, any numbertherebetween, or more) electrodes for positioning in the target tissueregion.

A system and method for delivering electric fields according to thepresent invention is described with reference to FIGS. 4A and 4B. Thesystem 70 includes an electrode array 72 that can be positioned in atarget tissue 82 (e.g., prostate tissue). Elongated needle electrodes inelectrode array 72 will include a distal portion and a proximal portion.The proximal portion of each electrode will be electrically connected toa system control unit or module 84, which includes electronics, storagemedia, programming, etc., as well as a power generator, for controlleddelivery of selected electrical fields to the target tissue 82. In use,electrode array 72 will be advanced through the prostate tissue (P) andto a desired position, as shown in FIG. 4A. Electrode positioning caninclude, for example, insertion and advancement through the skin andthrough the perineum of the patient. Electrode positioning andarrangement within the target tissue 82 can be precisely controlled andmay occur under the guidance of tissue imaging methodology (e.g.,ultrasound imaging, X-ray, CT, etc.). FIG. 4B illustrates across-section view of a target tissue 86 having a plurality ofpositioned needle electrodes 88.

A system for implementing a method according to the present invention isshown in FIGS. 5A and 5B, including transperineal access and positioningof electrodes using a positioning template, and delivery of electricfields to the prostate tissue. Referring to FIG. 5A, the system 90includes a plurality of elongated probes such as probe 92, having aproximal portion 94 and a distal portion 96. The distal portion 96includes a portion configured for delivery of the electrical field whenpositioned in the prostate tissue (P). The probe can be advanced throughthe skin and through the perineum of the patient so that the distalportion is positioned in the target area (e.g., prostate tissue (P)) ofthe patient. The proximal portion 94 of the probe 92 will beelectrically connected to a system control unit 98, as above, which caninclude electronics, storage media, programming, etc., as well as apower unit, for controlled delivery of selected electrical fields to thetarget tissue. As illustrated, the system 90 can optionally include aguide template 100 for controlled placement and positioning of the probe92 in the tissue of the patient. The system 90 can further include animaging device/system 102, which can include imaging systems describedfurther herein, which may be used for guidance and placement of theprobe 92. For example, the device 102 can include a distal portion 104including electronics and imaging components (e.g., ultrasonic scanningtransducer), which can be inserted in the patient's rectum (R) andpositioned against the rectal wall near the prostate (P). An exemplaryimaging device 102 can include those commonly used for diagnosticmedicine, such as ultrasonic imaging devices provided by Accuson, Inc.(Mountain View, Calif.). The guide template 100 can optionally bedesigned for coupling with the imaging device 102, such that guidetemplate 100 and the imaging device 102 form a single stable assembly.

A guide template 100, according to an exemplary embodiment of thepresent invention, is described in further detail with reference to FIG.5B. The template 100 includes a plurality of guides 106 (e.g., guideholes or via) through which the probes 92 can be inserted and distalportions of the probes advanced through the patient's tissue in acontrolled manner. Guides 106 can be disposed to form an array on thetemplate 100 and can be specifically sized to match or substantiallymatch the received probes 92, such that probes are positioned and heldin the desired position. As noted above, the template 100 can optionallybe designed for assembly with an imaging device 102, and may include animaging device receiving portion 108 through which the imaging devicecan be inserted.

Electrode positioning and energy delivery is further described withreference to FIGS. 6A through 6D). As described above with reference toFIGS. 4 and 5, the present invention can include insertion andpositioning of a plurality or array of individual electrodes, with theelectrodes being controlled individually or in groups and activated todeliver current field to the target tissue in a plurality of differentorientations and directions. Electrodes can be differentially activatedin various different pairs or groups such that the desired electricfield is delivered to the target tissue in a plurality of differentdirections. FIG. 6A illustrates use of an electrode pair as a basicfield delivery unit 110 of the electrode array, according to oneexample. As shown, distal portions 112, 114 of two electrodes (e₁ ande₂) of a plurality positioned in a target tissue 116 and activated as anelectrode pair or circuit, with the applied current substantiallycontained between the two. Thus, electrodes can be activated in abipolar configuration, with current flowing between electrodes (e.g.,between e₁ and e₂) and the tissue between the electrodes acting as aflow medium or current pathway between the electrodes. Controlledactivation of pairs or relatively small groups of electrodes in thismanner allows more precise control of the current applied to the tissue,containment of the applied field to the desired location, as wellcontrol of heating or limited temperature increase in the target tissue116, Several factors may lend to improved control of therapeutic effectsof the delivered fields according to the present invention. First, asdiscussed above activating electrode in pairs or groups in a bipolarconfiguration or so as to form a circuit allows the applied field tosubstantially be contained within the volume defined by the positionedelectrodes. Second, energy delivery can be selected (e.g., frequencyranges between about 50 kHz to about 300 kHz) such that tissue heatingoccurs substantially due to tissue resistance, relative to thefrictional heating observed at high frequencies (e.g., 500 kHz orgreater). High frequency/high friction type heating is typicallycharacterized by significant tissue temperature gradients throughout thetreated tissue, with substantially higher tissue temperatures occurringnear the electrode.

Another advantage of methods using the described electrode array orplurality of the present invention is that relative electrodepositioning can be limited to smaller distances so as to further allowmore precise control of the desired effect of the applied field on thetissue. Factors such as differential conductive properties andresistance or tissue impedance (e.g., differences in muscle, adipose,vasculature, etc.), as well as differential perfusion of blood throughvascularized tissue, can limit the ability to control and/or predicteffects of delivered current field traversing larger distances throughtissue. In the present invention, distances between activated electrodescan be limited to shorter distances, such as a few centimeters or less,for improved control and predictability of current effects (e.g., tissueheating, field delivery, orientation, etc) on the targeted tissue. Thus,activated electrodes in a pair or group can be spaced less than about 4cm apart, For example, adjacent electrodes of a pair or group willtypically be positioned within about 0.1 cm to about 2 cm of each other.Distances of about 0.5 cm have been shown to be particularly effectivein providing controlled and predictable field delivery, controlledtissue heating, as well as substantial therapeutic effect.

As described above, a plurality of electrodes can be positioned in thetarget tissue of the prostate of a patient and the electrodes can beactivated in pairs or groups to deliver the therapeutic current field todestroy cancerous tissue. A particular electrode of an array need not beconfined to a single unit, but can be activated at different times inconjunction with different electrodes of the plurality. For example,differential activation can include activating a specific or selectedseries of electrode groups in a particular or predetermined order. Inone embodiment, a series of selected pairs or groups can be activated inseriatim and/or in a predetermined order, with activation controltypically being determined by operation or instructions (e.g.,programming) of a control system or module. Sequences of groupactivations can be controlled and repeated, manually or by automation,as necessary to deliver an effective or desired amount of energy.

Such differential activation advantageously allows delivery of fieldsthroughout the target tissue and in a plurality of different directions.As shown in FIG. 6B, a simple four electrode grouping 118 of an arraycan be differentially activated in pairs, with each different pair ofelectrodes 120 providing a different field delivery and orientation(possible field flow/orientations are illustrated by arrows). Whileactivation of electrodes in discrete pairs provides simplicity,electrodes can be activated in groups for more diverse field orientationand deliver. For example, a delivery unit can include a centrallylocated electrode surrounded by spaced electrodes, with the appliedfield extending between the central electrode and the outer spacedelectrodes. In this manner, the outer electrodes can essentially definean ablation volume with the inner/central electrode positioned withinthe volume. Field delivery in this way is advantageously controlled andsubstantially contained within the ablation volume, FIGS. 6C and 6Dillustrate exemplary electrode positioning including outer electrodes122 and an inner or centrally located electrode 124. Electrodepositioning will not be limited to any particular configuration, andvarious arrangements will be possible.

FIG. 7 schematically illustrates a method 130 encompassed by the presentinvention. As in the embodiments described in FIGS. 4 and 5, forexample, a system of the present invention can include a plurality ofelectrodes that can be positioned in the target tissue or prostatetissue of a patient, with selected current delivery and application tothe tissue occurring by differential activation of various groups orpairs of electrodes, Thus, a method of the present invention, as shownin FIG. 7, can include positioning a plurality of electrodes in a targettissue of a patient at a first or initial treatment location (Step 132).The plurality can be positioned entirely within the patient's prostatetissue or may include positioning of at least some electrodes of theplurality at or beyond the prostate tissue margin. In some cases,positioning for initial current delivery may include advancingelectrodes through the perineum of the patient and to a distal mostportion of the prostate tissue nearest the patient's bladder. Electrodeadvancement and positioning may be aided or guided by tissue imagingtechniques. Once the desired initial treatment positioning of theelectrodes has been achieved, initial field delivery can occur. Asdescribed above (see, e.g., FIGS. 6A through 6D), current can bedelivered to the target region of the tissue in a plurality of differentdirections or current orientations be differentially selecting betweenand activating different pairs/groups of electrodes. Different groups orpairs of electrodes can be activated individually or in sequence, or aplurality of different groups can be activated simultaneously. Forexample, treatment can include selecting a first grouping or pairing ofelectrodes for activation, and delivering current between the selectedpairs/groups (Step 134). Current delivery can be cycled throughdifferent pairings or groupings of electrodes by discontinuing currentdelivery through the first selected grouping, and selecting a second orsubsequent grouping for activation (Step 136). Following cycling orselecting a different subsequent grouping, current is delivered betweenthe next selected electrode pair/group (Step 138). Following currentdelivery at the initial treatment positioning of the electrodes, the oneor more of the plurality can be removed from the tissue or the positionof the electrodes altered for a next phase of current delivery (Step140). For example, electrodes can be withdrawn a short distance in aproximal direction to alter the electrode penetration depth for a nextphase of current field delivery (Step 142). Current delivery andelectrode re-positioning can be repeated until the desired volume of thetissue has been treated.

Treatment time according to the present invention can be selected basedon a variety of factors, such as characterization of the tissue, energyapplications selected, patient characteristics, and the like. Energyapplication to a target tissue region during treatment according to thepresent invention can be selected from a few minutes to several hours.Though, effective treatment is expected to occur in about 5 minutes to90 minutes. Effective preferential destruction of cancerous prostatecells has been observed in less than one hour, and in many cases about15-30 minutes of energy application. Treatment can include a singleenergy delivery period or dose, or multiple phases or doses of energyapplication. As described above, electrodes can be positioned in a firstlocation and energy delivered, then moved to subsequent location(s) forsubsequent energy delivery. Treatment can occur in phases or repeated,and/or may be coupled with additional or alternative treatments orenergy delivery methods.

As described above, electrodes will include a distal portion having anelectrically active region for delivering the desired current field tothe target tissue. Various electrode configurations and designs can beutilized and the current invention is not limited to any particularelectrode design. Electrodes, for example, can be differentiallyinsulated such that current delivery occurs at a non-insulated or thinlyinsulated region of the electrode. FIG. 8A illustrates a straight needleelectrode 150 having an electrically active region 152 and a region 154,which is non-electrically active. The needle 150 can include anelectrically conductive material (e.g., stainless steel, silver, gold,etc.) having an insulating coating on region 154 and non-insulated onthe active region 152. Electrodes can include a single active region ora plurality of active regions, as shown in FIG. 8B having active regions156, 158. In addition to more rigid straight needle type electrodes,electrodes can include a deployable element that can be retractable andpositioned within a lumen of a catheter-type device, as shown in FIG.8C. The electrode element 160 can be curved (as shown) or can besubstantially straight or linear. Various needle/electrode sizes and/orconfigurations may be utilized, and can include, without limitation,needles ranging from about 15 to about 27 gauge in size.

As noted above, access to the target tissue or prostate tissue can begained through the urethra of the patient. Referring to FIG. 9, aurethral access system 170 according to the present invention isillustrated. The system 170 includes an elongated probe 172 that can beinserted in the urethra (U) of a patient via the penis (P), and advancedalong the urethra (U) to the desired location within the patient's body,specifically at a target location in the prostate tissue or gland (P).The probe includes a flexible catheter having an elongated shaft 174that can be bent or flexed while advanced into and through the urethra(U). The probe includes a distal tip 176, that can be shaped (e.g.,rounded) to minimize damage or trauma to the urethral wall duringpositioning or use. The probe 172 can optionally include a drainagelumen (not shown) that allows fluid communication between an area distalto the distal tip and the exterior or a proximal portion of the probe172, so as to allow draining or flushing of contents of the bladder (B)during treatment and use of the probe 172.

The urethral probe 172 includes a proximal end and a distal portionhaving an expandable member 178, such as a balloon configured forexpansion in the urethra (U) of the patient. The proximal end ispositioned outside the patient's body during use, and can include a hubor handle 180 that can be coupled to a controller or control unit, andpower source 182. The expandable member 178 includes conductiveelectrode elements 184 patterned or disposed on an outer surface of theexpandable member 178, The probe will include an elongated body 174extending from the proximal portion of the device to the distal portion,and the elongated body can include an inner lumen or passage withelectrical coupling members, such as insulated wires, for coupling theelectrode elements 184 of the expandable member 178 to the proximal endand/or an externally positioned controller and/or power source 182. Asindicated in FIG. 9, the urethra of the patient (U) will include alength (l) passing through the prostate tissue (P) until reaching thebladder (B). The expandable member 178 of the probe 172 can includevarious shapes and configurations selected to span any portion of thelength (l). The expandable member 178 can be configured to span theentire length (l) (or more) or may be sized to span less than the entireportion. The expandable member 178 may be positioned at any portionalong the length (l) during treatment, as well as elsewhere along thepatient's urethra (U), including portions at or adjacent to locationswhere the urethra (U) enters or exits the prostate tissue (P) area.

The probe will be designed to include electrode elements that can bepositioned in the desired location and used for delivery of electricfields to the target tissue for treatment according to the presentinvention. Various embodiments of electrode elements can be included inthe present invention and the probe can be designed or configured fordelivery of electrical fields, for example, between the expandablemember and opposing electrode(s) (e.g., secondary electrodes) positionedin or in the vicinity of the prostate tissue, with current fields insome embodiments established between electrodes and typically in aplurality of directions (e.g., radially) through a volume of tissue.Electrode elements 184 of the expandable member 178 can includeconductive material deposited or patterned on a surface or at least aportion of the expandable member 178 that is brought into contact withthe walls of the urethra (U) during treatment. In one embodiment, theexpandable member 178 can be configured in a deployable configuration,such that the expandable member 178 may be positioned within the probeshaft and then deployed from the probe (e.g., from the distal end or tipof the probe) and expanded at the desired location. For example, theexpandable member can be positioned or disposed within in the probeshaft or portion of the elongate body (e.g., shaft lumen) duringadvancement and positioning of the probe, and deployed from the probeonce a desired position in the patient's urethra has been reached.Alternatively, in another embodiment, the expandable member or balloon(e.g., electrode patterned balloon) can be coupled and positioned alongthe length of the probe on an outer surface, with inflation or expansionof the expandable member controlled by an external pressure sourcecoupled to the proximal portion of the probe.

A probe may include one or more electrodes (e.g., secondary electrodes)that can be positioned within the probe and deployed from the probe andinto the prostate tissue. For example, such secondary electrodes can bepositioned in the probe shaft or body during advancement and positioningof the probe, and deployed from the probe once a desired position hasbeen reached. Deployable probes can include needle-like electrodes,which can include a shape memory metal and configured to assume adesired shape when deployed, e.g., as discussed further below.

During use, field delivery can occur with current flow between anelectrode elements of the urethral probe and electrode(s) spaced fromthe urethral probe, such as electrodes positioned in the prostate tissueor in the rectal area. As above, electrode elements, includingelectrodes of the expandable member, will be connected to an externalpower source 182 or power unit (e.g., power source of control system orunit), which will include a means of generating electrical power foroperation of the system and probe, and application of electrical currentto the target tissue as described herein. The power unit can include orbe operably coupled to additional components, such as a control unit,driver unit, user interface, and the like (see, e.g., infra).

System 170 further includes an imaging device 186, such as an ultrasonicimaging probe, for providing images of tissues for example duringpositioning and/or use of the probe 172. The device 186 includes adistal imaging portion 188 including electronics and imaging components(e.g., ultrasonic scanning transducer), which can be inserted in thepatient's rectum (R) and positioned against the rectal wail near theprostate (P). Imaging device 186 can include those commonly used fordiagnostic medicine (see, e.g, above). The imaging portion 188 can scana region of the tissue to generate an image of the tissue, rectal wall,prostate (P), urethra (U), and/or the probe located in the patient'surethra (U). The imaging device 186 can be connected to an imageprocessing unit 190 and a display unit 192, as is common practice. Inuse, the display 192 provides images (e.g., real-time ultrasonic images)of the prostate (P) with the position of the probe 172 relative to theprostate (P) and target area, the bladder (B), etc. to help guide orconfirm positioning of the probe 172 within the prostate (P) prior todelivery of treatment energy.

As discussed above, a probe of a system, e.g., as illustrated in FIG. 9,will include electrode element 184 patterned or otherwise disposed on anexpandable member or balloon 178 disposed on a distal portion of theprobe 172. A probe can include a catheter probe having a shaft and adistally positioned balloon member having electrode elements disposed(e.g., deposited, patterned, etc.) thereon. The balloon can be coupledto one or more fluid sources positioned externally, as well as apressure source and/or controller for inflation and deflation of theballoon. In one embodiment, the balloon can be configured such that afluid can be circulated through the balloon and may be utilized tofurther effect or control temperature of tissues proximate to theballoon, The probe further includes a proximal hub 180 that can includeone or more electrical connections for coupling the electrode elementsto an external power source and/or control unit 182, as well as fluidconnections for fluidic access and control of balloon actuation andinflation, as well as circulation of fluid (e.g., cooling fluid) throughthe balloon. In an embodiment where the probe 172 further includes oneor more deployable electrodes, actuation and positioning of suchdeployable electrodes can be controlled from the proximal end of theprobe, such as through the hub 180. In other embodiments, current flowcan extend between electrode elements 184 of the expandable member 178positioned in the patient's urethra (U) and one or more electrodeelements (e.g., secondary electrodes) spaced from the positionedexpandable member 178, and may be separate from the urethral probe, andpositioned on an opposing side of the urethral wall. For example, needleelectrodes can be separately advanced through the perineum of thepatient and positioned within the prostate tissue (P) around the urethra(U), with energy delivery establishing current flow between electrodeelements of the urethral probe and needle electrodes positioned in theprostate tissue (P). In yet another embodiment, electrode elements(e.g., electrodes disposed on an expandable balloon) can be positionedin the rectal cavity adjacent to the rectal wall, with current flowestablished between electrode elements of the urethral probe andelectrode elements of the rectally positioned device.

In yet another aspect, access and delivery of the desired current may begained through the rectal cavity. An energy delivery probe can beinserted into the rectum of a patient and electrodes positioned adjacentto the rectal wall or advanced through the rectal wall and into theprostate tissue of the patient. Various probe and/or electrodeconfigurations may be suitable for delivery of the current in accordancewith the present invention. A probe can include, for example, elongateddevice or catheter with one or more needle-like electrodes including,e.g., electrodes deployable from a catheter lumen. Alternatively, anenergy delivery probe can include one or more inflatable devices orballoons having electrode patterns disposed on a surface. Such balloonsmay be similar to those described above with respect to transurethralaccess and current delivery. Rectal probes can be utilized in isolation,e.g., with electrodes of the rectal probe forming discrete energydelivery units (e.g., pairs or groups of bipolar electrodes), orelectrodes of a rectal probe can operate in conjunction with otherelectrodes, such as electrodes of transuerethral probe or elongateelectrodes inserted across the perineum of the patient. In the lattercase, electrodes of the trans-rectal probe and separately positionedprobe can be operated in bipolar mode such that current flow isestablished across tissue separating the different devices, and betweenthe electrodes of the different devices.

A trans-rectal approach, according to one embodiment of the presentinvention, is described with reference to FIGS. 10A and 10B. A currentdelivery probe 200 can be inserted into the rectal cavity (R) of apatient, and the probe and/or one or more electrodes 202 of the probecan be advanced through the rectal wall and into the prostate tissue(P). The probe 200 can include a catheter having an inner lumen, withone or more electrodes 202 deployable from a distal portion of thecatheter. One advantage of such an approach is that the probe 200 can bemore easily located or positioned at the desired location foradvancement and delivery of electrode elements 202 to the desiredlocation. A user or physician, for example, can access the rectal cavityand position the probe distal end by manipulation by hand or one or morefingers 204. The probe 200 can include a plurality of deployableelectrodes 202 that can be positioned in the prostate tissue (P) so asto establish current flow in a plurality of different directions, suchas with a radial field application. As shown in FIG. 10B, for example,electrodes can include a plurality of outer electrodes 206, 208, 210deployed and positioned to form or define an ablation volume, with anelectrode 212 positioned within the volume. Current flow can beestablished between the centrally located electrode 212 and the outerelectrodes 206, 208, 210 for radial field application and establishingcurrent flow in a plurality of different directions. Treatment canfurther include use of an imaging device (not shown), such as anultrasound imaging device as described above, which can be inserted andpositioned in the rectal cavity (R) separately and/or in conjunctionwith other components (e.g., probe) of an energy delivery system of thepresent invention.

A system according to an embodiment of the present invention isdescribed with reference to FIG. 11. The system 300 can includeincorporated therewith any device of the present invention for deliveryof energy to the patient, and includes a power unit 310 that deliversenergy to a driver unit 320 and than to electrode(s) of an inventivedevice. The components of the system individually or collectively, or ina combination of components, can comprise an energy source for a systemof the invention. A power unit 310 can include any means of generatingelectrical power used for operating a device of the invention andapplying electrical current to a target tissue as described herein. Apower unit 310 can include, for example, one or more electricalgenerators, batteries (e.g., portable battery unit), and the like. Oneadvantage of the systems of the present invention is the low powerrequired for the ablation process. Thus, in one embodiment, a system ofthe invention can include a portable and/or battery operated device. Afeedback unit 330 measures electric field delivery parameters and/orcharacteristics of the tissue of the target tissue region, measuredparameters/characteristics including without limitation current,voltage, impedance, temperature, pH and the like. One or more sensors(e.g., temperature sensor, impedance sensor, thermocouple, etc.) can beincluded in the system and can be coupled with the device or systemand/or separately positioned at or within the patient's tissue. Thesesensors and/or the feedback unit 330 can be used to monitor or controlthe delivery of energy to the tissue. The power unit 310 and/or othercomponents of the system can be driven by a control unit 340, which maybe coupled with a user interface 350 for input and/or control, forexample, from a technician or physician. The control unit 340 and system300 can be coupled with an imaging system 360 (see above) for locatingand/or characterizing the target tissue region and/or location orpositioning the device during use.

A control unit can include a, e.g., a computer or a wide variety ofproprietary or commercially available computers or systems having one ormore processing structures, a personal computer, and the like, with suchsystems often comprising data processing hardware and/or softwareconfigured to implement any one combination of) the method stepsdescribed herein. Any software will typically include machine readablecode of programming instructions embodied in a tangible media such as amemory, a digital or optical recovering media, optical, electrical, orwireless telemetry signals, or the like, and one or more of thesestructures may also be used to transmit data and information betweencomponents of the system in any wide variety of distributed orcentralized signal processing architectures.

Components of the system, including the controller, can be used tocontrol the amount of power or electrical energy delivered to the targettissue. Energy may be delivered in a programmed or pre-determined amountor may begin as an initial setting with modifications to the electricfield being made during the energy delivery and ablation process. In oneembodiment, for example, the system can deliver energy in a “scanningmode”, where electric field parameters, such as applied voltage andfrequency, include delivery across a predetermined range. Feedbackmechanisms can be used to monitor the electric field delivery inscanning mode and select from the delivery range parameters optimal forablation of the tissue being targeted.

Systems and devices of the present invention can, though notnecessarily, be used in conjunction with other systems, ablationsystems, cancer treatment systems, such as drug delivery, local orsystemic delivery, surgery, radiology or nuclear medicine systems, andthe like. Another advantage of the present invention, is that treatmentdoes not preclude follow-up treatment with other approaches, includingconventional approaches such as surgery and radiation therapy. In somecases, treatment according to the present invention can occur inconjunction or combination with therapies such as chemotherapy.Similarly, devices can be modified to incorporate components and/oraspects of other systems, such as drug delivery systems, including drugdelivery needles, electrodes, etc.

The following examples are intended to illustrate but not limit theinvention.

EXAMPLE

The present example describes a study designed to evaluate efficacy ofdifferent treatment parameters using the electric field delivery andablation technology as described herein in the treatment of a humanprostate cancer (CaP) xenograft model.

Design

Sixty 4 to 6-week old male CB-17 SCID mice were injected subcutaneouslyon the right flank with 2*10⁶ cells of the C4-2B CaP cell line. Afterinjection, animals enrolled once tumor volumes reached 200 mm³ (˜3-4weeks) and randomized into one of five groups using the followingdesign: 1) Control group—received placement of probe without current(n=10); 2) a groups receiving 15 mAmp for 15 min (n=13); 3) a groupreceiving 15 mAmp for 60 min (n=9); 4) a group receiving 25 mAmp for 15min (n=10); and 5) a group receiving 25 mAmp for 60 min (n=10). Micewere treated with direct application of a low power, intermediatefrequency (e.g., about 100 kHz) field through percutaneous placement ofa probe (e.g., as shown in FIGS. 2A-2C) in a fashion that affording thegreatest tumor coverage. The day of treatment was designated as Day 1.The day prior to the treatment day was designated as Day −1.

A subsets of animals were sacrificed 7 days after treatment forhistopathological evaluation of tumors. The remaining mice weresacrifice 14 days or more after treatment. Animals that had completedestruction of their tumors were observed for up to 30 days posttreatment for recurrence. Tumor volumes were measured twice weekly andprostate specific antigen (PSA) levels were measured once a week.

The probe used was of the triangle configuration with a central anodeand three outer cathodes (see, e.g., FIGS. 2A-2D). The radius of theprobe from anode to cathode was three millimeters in one example. Aseparate group was evaluated using a four millimeter anode to cathodespacing (see results illustrated in FIG. 13). The electrode probe wascoupled to a System Control Module (SCM) designed to generate, deliver,monitor and control the therapeutic field within the specified treatmentparameters. The SCM included of an integrated direct current (DC)battery power source, an alternating current (AC) inverter, a signalgenerator, a signal amplifier, an oscilloscope, an operator interfacemonitor, and a central processing unit (CPU). The SCM was batterypowered and isolated from ground. AC current was derived from theintegrated power inverter. An intermediate frequency (about 100 kHz)alternating current, sinusoidal wave form signal can be produced fromthe signal generator. The signal is amplified to a current range of 5 mAto 40 mA and voltage of up to 20 Vrms. Total power output is less than 1watt. Field characteristics including wave form, frequency, current andvoltage are monitored by an integrated oscilloscope. Scope readings aredisplayed on the operator interface monitor. An integrated CPU monitorsoverall system power consumption and availability and controls theoutput of the signal generator and amplifier based on the treatmentparameters input by the operator.

Prostate Tumor Xenograft Model

The C4-2B CaP cell line was obtained and implanted. This is ancastration-resistant CaP cell line derived from a bony metastasis of theLNCaP cell line. This line was maintained under standard conditions andpropagated when necessary. Tumor measurement were done with hand heldcaliper begin once tumors become palpable and twice weekly thereafter.

Animals included CB-17 SCID male mice were obtained from Fox Chase SCIDmice, Charles River, Wilmington, Mass. Animals were eartagged andchecked for health on arrival Nov. 7, 2007 and group housed (fiveanimals per cage) at the vivarium. Animals were acclimated to thefacility for 7 days before beginning the experiment. Statisticalanalyses were performed using unpaired student t-tests and ANOVA (PrismGraphpad, Graphpad Software, San Diego, Calif.). Statisticallysignificance results were designated as P≦0.05. After fixation, tumorswere serially sectioned in 2-3 mm increments from which 5 micron thickslides were cut and used for histopathology analysis.

Dose Groups

Animals were randomly sorted and assigned into five different treatmentgroups (see Table 1) and randomized.

TABLE 1 Treatment Groups and Animal Assignment Sacrifice ScheduleAnimals Treatment Treatment (Animal Number) Group (Numbers) ConditionsDuration Day 7 Day 14 1 12 0 mAmp XX min 1-6  7-12 2 12 15 mAmp 15 min13-18 19-24 3 12 15 mAmp 60 min 25-30 30-36 4 12 25 mAmp 15 min 37-4243-48 5 12 25 mAmp 60 min 49-54 55-60

All animals were closely observed daily for signs of lethargy, weightloss, paralysis, dyspnea, cyanosis, mucopurulent discharges,incontinence, diarrhea, changes in coat or body condition, or any otherhealth problems that could indicate that the animal was becomingmoribund (as defined by IACUC guidelines). All observations weredocumented and members of the research staff were notified if anyabnormalities were found. Any animal found with apparent health problemswas monitored at additional times, as needed. Any animal appearingmoribund was promptly euthanized.

Mice were bleed (˜20uL) from the tail vein once weekly starting withenrollment. Serum was removed after centrifugation for 8 min at 10000RPM. PSA levels were then determined using IMx Total PSA Assay, AbbottLaboratories, Abbott Park, Ill. Intra-tumoral temperature measurementswere made using thermocouples positioned in the tissue. Baselinetemperature measurements were taken prior to application of power and at15 minute intervals. Current delivery was selected to avoid damage dueto severe temperature elevation (e.g., exceeding 50 degrees C.).

Results

Animals tolerated the procedure well with no observable adverse sideeffects attributed to the application of the treatment. The animals thatreceived 15 mAmp of current applied to their tumors demonstrated a17±4.7% (mean±SEM) decrease in enrollment tumor volume at the lowestnadir following treatment. These reductions were greater than (thoughnot significantly different) from those seen in the control group(Control−10±6.9%, p=0.436). When comparing the groups receiving 15mAmp/15 min vs. 15 mAmp/60 min there was no significant difference totumor volume reductions (p=0.85). The animals that had 25mAmp of currentapplied to their tumors had a 62±9.4% decrease in tumor volume at theirlowest nadir. This is a significant decrease in tumor volume compared toboth the control group (p=0.001) and 15 mAmp treated animals (p<0.001).There were no differences in tumor volume reduction measured between thegroup receiving 25 mAmp for 15 min and the group receiving 25 mAmp for60 min (p=0.704). It was noted that 6/20 animals treated with 25 mAmpdemonstrated a complete ablation/destruction of the tumor. Results oftreatment on tumor volume are illustrated in FIG. 12A. Results oftreatment on tumor volume using the four millimeter probe compared tocontrol is shown in FIG. 13. Using the 4 mm probe configuration with 33mAmp treatment, approximately half of the tested animals had completeablation/destruction of the tumor.

Prostate-Specific Antigen

PSA levels generally tracked well with treatment effectiveness and tumorvolume reductions. PSA levels normalized to enrollment levels are shownin FIG. 12B. Normalized levels were examined at 14 days from enrollment.Sonic non-statistically significant reduction was seen in PSA levels inthe 15 mAmp treated animals compared to control (4.4±1.1 vs. 6.1±4.3,p=0.634). The normalized PSA levels in the 25 mAmp treated at 14 dayswas 0.67±0.3 which represents a significant reduction compared to the 15mAmp treated animals(p=0.005). Due to the large variation in the controlgroup PSA levels, no statistical difference could be found between the25 mAmp animals and control animals (though trend differences wereobserved). No significant differences in PSA levels were measuredbetween groups receiving the same current but a different timeintervals.

Tissue Temperature

Intra-tumoral temperatures were measured immediately prior to and duringeach treatment in most study groups. Animal body temperature wastypically around 37° C. Tumor tissue temperature of animals underanesthesia dropped below normal average body temperature. Duringtreatment, the 15 mAmp treatment groups rose to a maximum temperature of36±0.6° C. (mean SEM). This represents a 6.5±1.1° C. elevation abovebaseline temperatures during treatment. The maximum temperature in the25 mAmp treatments groups was significantly higher compared to the 15mAmp treated groups (25 mAmp: 44±0.6° C.; p<0.001) with significantlyhigher elevations in temperature above baseline vs. 15 mAmp treatedgroups (15±0.6° C.; p=<0.001).

The described low-power, mild hyperthermia treatment demonstratedsignificant tumoricidal capabilities. The results show that efficacy isbased on the current applied and with effective treatment occurring inshortest tested treatment times. Tissue heating due to treatment waslimited to average treatment temperatures of about 44° C., which wouldseem to preclude as a cytotoxic factor effects of more extremetemperature application characterized by tissue charring and substantialprotein cross-linking typically observed at temperatures well in excessof 50° C.

Further, elevations in temperature to this level have typically requiredfar greater lengths of treatment than the observed treatment times shownto have effectiveness in this study. It is possible that both theelevations in temperature along with factors such as the application ofalternating electrical current and/or field orientation cumulatively orsynergistically allow for shorter time intervals necessary to derive atthe desired tumor ablating effect.

It is further noted that further refinements and/or customization ofdelivery probes or positioned electrodes to individual tumors beingtreated may further improve treatment results. In some subjects,electrodes did not encompass the entire tumor or in some cases wereentirely contained within the tumor margin and, therefore, less than theentire tumor was treated in such instances. Complete tumor destructionwas seen in some animals and was observed more likely in instances wherethe tumor was more thoroughly contained within the treatment volume.Further, as a group, improved results were observed in the study groupusing the larger sized probe with 4 mm anode/cathode spacing, where onaverage tumors were more completely treated.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. Numerous different combinations arepossible, and such combinations are considered part of the presentinvention.

What is claimed is:
 1. A method of delivering electric fields to aprostate tissue of a patient, comprising: positioning a plurality of anumber of electrodes together through an external guide array templateto penetrate a target tissue region comprising the prostate tissue,wherein each of the plurality of electrodes is substantially straight,elongated and penetrates and extends through the external guide arraytemplate and into the prostate tissue substantially parallel with othersubstantially straight elongated electrodes of the plurality ofelectrodes; and using the plurality of substantially straight elongatedand substantially parallel electrodes extending through the externalguide array to establish an electrical alternating current flow betweenthe plurality of electrodes in a plurality of different positions andorientations to define a a treatment volume of the prostate tissue,wherein the alternating electrical current flow further comprises anumber of electrical coupling paths having a field strength less than 50Volts per centimeter between the plurality of electrodes, the number ofelectrical coupling paths having the field strength less than 50 Voltsper centimeter greater than the number of substantially straight andsubstantially parallel elongated electrodes extending through theexternal guide array template defining the treatment volume, so as topreferentially ablate one or more of cancerous or hyperplasic cellscompared to healthy cells in the treatment volume.
 2. The method ofclaim 1, wherein establishing the electrically alternating current flowcomprises applying an alternating electrical current to the volume toprovide an electric field extending radially outward from a current flowcenter.
 3. The method of claim 2, wherein the electric field extendingradially outward from a current flow center is established by theplurality of electrodes positioned to define an ablation volume, withthe plurality of electrodes positioned around the volume activated ingroups to establish current flow between the plurality of electrodes. 4.The method of claim 1, further comprising positioning a plurality ofsecondary electrodes to at least partially define an ablation volumecomprising the target tissue region, positioning a center electrodewithin the ablation volume, and establishing a current flow fieldbetween the center electrode and the secondary electrodes extendingradially outward from a current flow center.
 5. The method of claim 1,wherein positioning the plurality of electrodes comprises advancing aprobe comprising the plurality of electrodes to the target tissueregion.
 6. The method of claim 5, wherein the probe is advanced througha surgical incision, a percutaneous puncture, a perineal, atransurethral, or transrectal access procedure.
 7. The method of claim1, wherein the plurality of electrically alternating current flows heatsthe target tissue region to an average temperature from about 40 degreesC. to about 48 degrees C.
 8. The method of claim 1, further comprisingsurgically removing at least a portion of the prostate or performing abrachytherapy procedure following electric-current delivery.
 9. Themethod of claim 1, further comprising monitoring a patient's PSA levelfollowing electric current delivery to detect prostate tissue ablation.10. The method of claim 1, wherein the positioning comprises positioningelectrodes in the prostate tissue and adjacent to or around the urethraof the patient for treatment of benign prostatic hyperplasia (BPH). 11.The method of claim 1, comprising delivering electrical currentsubstantially throughout the volume of the patient's prostate duringtreatment.
 12. The method of claim 1, comprising maintaining for aperiod of treatment an average target tissue region temperature below 50degrees C.
 13. The method of claim 1, comprising maintaining for aperiod of treatment an average target tissue region temperature fromabout 40 degrees C. to about 48 degrees C.
 14. The method of claim 1,comprising maintaining for a period of treatment an average targettissue region temperature from about 42 degrees C. to about 45 degreesC.
 15. A system for preferential destruction of cancerous orhyperplastic cells of a prostate tissue of a patient, comprising: anexternal guide array template; a plurality of a number of electrodesarranged for advancement and positioning together through the externalguide array template into a target tissue region of the prostate tissue,wherein each of the plurality of electrodes is substantially straight,elongated and sized and shaped to penetrate and extend into the prostatetissue substantially parallel with other substantially straightelectrodes of the plurality of electrodes; wherein the external guidearray template comprises guides sized and shaped to receive theplurality of electrodes and position the electrodes in tissue in asubstantially parallel arrangement to define a treatment volume; acontrol system comprising a power source coupled to the electrodes, anda computer readable storage media comprising instructions that_(;) whenexecuted, cause the control system to: provide electrical alternatingcurrent to the plurality of electrodes so as to establish an alternatingcurrent flow in a plurality of different positions and orientationsbetween the plurality of electrodes through a treatment volume of theprostate tissue, wherein the alternating electrical current flow furthercomprises a number of electrical coupling paths having a field strengthless than 50 Volts per centimeter between the plurality of electrodes,the number of electrode coupling paths having the field strength lessthan 50 Volts per centimeter greater than the number of substantiallystraight and substantially parallel elongated electrodes extendingthrough the guide array template defining the treatment volume, so as topreferentially destroy one or more of the cancerous or hyperplasticcells compared to healthy cells in the treatment volume.
 16. The systemof claim 15, herein the plurality of electrodes comprises three or moresecondary electrodes positioned to at least partially define an ablationvolume and a center electrode within the ablation volume, the pluralityof electrodes positioned such that during energy application a currentflow field is established between the center electrode and the secondaryelectrodes extending radially outward from a current flow center. 17.The system of claim 16, wherein the plurality of electrodes is coupledto a housing of a probe in a fixed position.
 18. The system of claim 15,further comprising a feedback unit for detecting temperature in thetarget tissue region.
 19. The system of claim 18, wherein the controlnit and feedback unit are coupled so as to maintain an average targettissue region temperature from about 40 degrees C. to about 48 degreesC. during treatment comprising energy delivery.
 20. The system of claim15, further comprising an imaging system.
 21. A method of deliveringelectric fields to a prostate tissue of a patient, comprising:positioning a plurality of a number of electrodes together through anexternal guide array template to penetrate a target tissue regioncomprising the prostate tissue, wherein each of the plurality ofelectrodes is substantially straight, elongated and penetrates andextends into the prostate tissue spaced laterally and substantiallyparallel relative to other substantially straight electrodes of theplurality of electrodes, and wherein the plurality of electrodes definesa treatment volume in the prostate tissue; and using the plurality ofelectrodes to establish an alternating electrical current flow in aplurality of different positions and orientations between the pluralityof electrodes through the treatment volume of the prostate tissue,wherein the alternating electrical current flow further comprises anumber of electrical coupling paths having a field strength less than 50Volts per centimeter between the plurality of electrodes, the number ofelectrical coupling paths having the field strength less than 50 Voltsper centimeter greater than the number of substantially straight andsubstantially parallel elongated electrodes extending through the guidearray template defining the treatment volume, so as to induce mildhyperthermic heating of the treatment volume and preferentially destroyone or more of cancerous cells or hyperplasic cells compared to healthycells in the treatment volume.
 22. The method of claim 1, wherein usingthe plurality of electrodes comprises differentially activating inseriatim (a) a first activation configuration of the plurality ofelectrodes so as to induce a first voltage field with a firstorientation at a first location within the volume; and (b) a secondactivation configuration of the plurality of electrodes so as to inducea second voltage field with a second orientation at the location, thesecond orientation different from the first orientation at the location.23. The method of claim 1, wherein the plurality of electricallyalternating current flow heats the target tissue region to an averagetemperature of no more than about 50 degrees C.
 24. The system of claim15, wherein the control system is configured to differentially activatein seriatim (a) a first activation configuration of the plurality ofelectrodes so as to induce a first voltage field with a firstorientation at a first location within the volume; and (b) a secondactivation configuration of the plurality of electrodes so as to inducea second voltage field with a second orientation at the location, thesecond orientation different from the first orientation at the location.25. The system of claim 15, wherein the control unit and feedback unitare coupled so as to maintain an average target tissue temperature of nomore than about 50 degrees C. during treatment.
 26. The method of claim21, wherein using the plurality of electrodes comprises differentiallyactivating in seriatim (a) a first activation configuration of theplurality of electrodes so as to induce a first voltage field with afirst orientation at a first location within the volume; and (b) asecond activation configuration of the plurality of electrodes so as toinduce a second voltage field with a second orientation at the location,the second orientation different from the first orientation at thelocation.
 27. The method of claim 21, wherein the mild hyperthermicheating includes heating the treatment volume to an average temperatureof no more than about 50 degrees C.